biostudies-literatureGuney INCRR NIH HHSNIA NIH HHSNIGMS NIH HHS3645-50https://www.ebi.ac.uk/biostudies/studies/S-EPMC1450136biostudies-literatureUnknown103(10)Increased mitogenic signaling by positive effectors such as Ras or Myc can trigger senescence in normal cells, a response believed to function as a tumor-suppressive mechanism. We report here the existence of a checkpoint that monitors hypoproliferative signaling imbalances. Normal human fibroblasts with one copy of the c-myc gene inactivated by targeted homologous recombination switched with an increased frequency to a telomere-independent senescent state mediated by the cyclin-dependent kinase inhibitor p16(INK4a). p16(INK4a) expression was regulated by the Polycomb group repressor Bmi-1, which we show is a direct transcriptional target of c-Myc. The Myc-Bmi circuit provides a mechanism for the conversion of environmental inputs that converge on c-Myc into discrete cell-fate decisions coupled to cell-cycle recruitment. A mechanism for limiting the proliferation of damaged or otherwise physiologically compromised cells would be expected to have important consequences on the generation of replicatively senescent cells during organismal aging.Proceedings of the National Academy of Sciences of the United States of AmericaReduced c-Myc signaling triggers telomere-independent senescence by regulating Bmi-1 and p16(INK4a).PMC1450136P20 RR015578P20 RR15578R01 GM41690R01 GM041690R01 AG16694R01 AG016694Sedivy JMGuney IWu SfalseReduced c-Myc signaling triggers telomere-independent senescence by regulating Bmi-1 and p16(INK4a).Increased mitogenic signaling by positive effectors such as Ras or Myc can trigger senescence in normal cells, a response believed to function as a tumor-suppressive mechanism. We report here the existence of a checkpoint that monitors hypoproliferative signaling imbalances. Normal human fibroblasts with one copy of the c-myc gene inactivated by targeted homologous recombination switched with an increased frequency to a telomere-independent senescent state mediated by the cyclin-dependent kinase inhibitor p16(INK4a). p16(INK4a) expression was regulated by the Polycomb group repressor Bmi-1, which we show is a direct transcriptional target of c-Myc. The Myc-Bmi circuit provides a mechanism for the conversion of environmental inputs that converge on c-Myc into discrete cell-fate decisions coupled to cell-cycle recruitment. A mechanism for limiting the proliferation of damaged or otherwise physiologically compromised cells would be expected to have important consequences on the generation of replicatively senescent cells during organismal aging.2006-01-01T00:00:00Z2006 Mar2026-04-29T19:50:01.216Z2019-03-27T01:26:20ZS-EPMC14501361653744910.1073/pnas.0600069103